The Role of Drosha in the Pathogenesis of Alzheimer's Disease

Drosha 在阿尔茨海默病发病机制中的作用

• 批准号: 9323608
• 负责人: ZIXU MAO
• 金额: $ 45.36万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323608
• 关键词: Aging; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid beta-Protein; Animals; Autopsy; Biogenesis; Brain; Brain Diseases; Calpain; Cell Death; Cell Nucleus; Cell physiology; Cells; Cellular Stress; Cessation of life; Chronic; Cleaved cell; Complex; Coupled; Data; Degenerative Disorder; DiGeorge Syndrome; Disease; Distributional Activity; Environment; Enzymes; Functional disorder; Genes; Genetic; Genetic Transcription; Goals; Health; Homeostasis; Human; Individual; Knock-out; Link; MAP Kinase Gene; MAPK14 gene; Mediating; Methods; MicroRNAs; Microprocessor; Molecular; Mus; Names; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Nuclear; Nuclear Export; Nucleotides; Outcome; Parkinson Disease; Pathogenesis; Pathogenicity; Pathologic; Pathologic Processes; Pathway interactions; Peptide Hydrolases; Phosphorylation; Phosphorylation Inhibition; Phosphotransferases; Physiological; Play; Population; Process; Proteins; Rattus; Regulation; Research; Research Personnel; Ribonuclease III; Role; Senile Plaques; Series; Signal Pathway; Signal Transduction; Small RNA; Stress; Structure; Testing; Toxic effect; Transcript; Transgenic Organisms; Translating; Treatment Efficacy; Untranslated RNA; abeta oligomer; abeta toxicity; biological adaptation to stress; brain cell; human disease; hyperphosphorylated tau; insight; neurotoxicity; novel; progressive neurodegeneration; protein complex; tau Proteins; therapeutic target

Neurons are highly sensitive to changes in their environment, and have developed dynamic adaptive processes to sense and copy with stress caused by such changes. The long-term goal of our research is to understand the mechanisms by which neurons respond to stress. MiRNAs (microRNAs) are a recently discovered class of non-coding small RNAs that are involved in regulating many cellular processes including stress. Dysfunction of miRNAs has been implicated in many pathological processes. MiRNA biogenesis is controlled by several tightly coupled sequential steps governed by multiple protein complexes and subjected to intricate regulation. The entire process is initiated in the nucleus by the conversion of the long primary miRNA transcripts to the hairpin structured precursor miRNA (pre-miRNAs) by the RNase III enzyme Drosha. Whether Drosha itself is a direct regulatory target is unknown. A growing body of data suggests that stress conditions and miRNAs are highly intertwined at several levels. However, signals and pathways directly modulating Drosha under either physiological or pathological stress condition remain to be identified. There are multiple lines of evidence indicating that miRNAs are especially important to the brain function and modulate pathways and key genes relevant to genetic and sporadic AD pathogenesis. Many of these miRNAS are themselves altered in AD. Furthermore, inhibiting miRNA biogenesis by conditionally knocking out Dicer in neurons, which blocks miRNA biogenesis at a step downstream of Drosha, causes mice to develop progressive neurodegeneration and AD-like tau hyperphosphorylation. This offers perhaps the strongest evidence for a potential link between miRNA biogenesis and AD. However, how these findings translate into animal AD models and human disease remains to be tested. Recently, we have revealed that a variety of stress conditions exert a direct and tight control of Drosha. This involves a stress-induced, p38 MAPK dependent phosphorylation and inhibition of Drosha, and loss of Drosha triggers cell death under stress (Molecular Cell in press). In a series of preliminary studies, we have extended this set of key findings to primary cortical neurons and shown that a) stress signals cause p38 MAPK-mediated direct phosphorylation and inhibition of Drosha in neurons; b) Aβ appears to engage this pathway and reduces the level of Drosha in primary cortical neurons; c) increasing Drosha protects neurons from Aβ-induced toxicity; and d) the levels of the nuclear Drosha are significantly reduced in the cortex of a transgenic AD rat and the postmortem AD brains. Together, these highly significant findings support an intriguing hypothesis that Aβ signals via p38 MAPK-Drosha pathway to inhibit miRNA biogenesis and interfere neuronal homeostasis and survival. Loss of Drosha may underlie in part the neurodegenerative process in AD. We propose to use a combination of molecular and cellular methods to assess whether loss of Drosha underlies Aβ-induced toxicity and pathogenesis using cultured primary neurons, a new established rat model of Alzheimer's disease, and human postmortem AD brains.

神经元对周围环境的变化高度敏感，并具有动态适应性 这些变化引起的压力使感知和复制的过程变得困难。我们研究的长期目标是 了解神经元对压力的反应机制。miRNAs（microRNAs）是近年来 发现了一类非编码小RNA，参与调节许多细胞过程，包括 应力miRNAs的功能障碍涉及许多病理过程。miRNA的生物起源是 由多个蛋白质复合物控制的几个紧密耦合的顺序步骤控制， 复杂的规则。整个过程是在细胞核中由长的初级miRNA的转化开始的 通过RNase III酶Drosha将转录物转化为发夹结构的前体miRNA（pre-miRNA）。是否 Drosha本身是否是直接监管目标尚不清楚。越来越多的数据表明， 而miRNAs在几个水平上高度交织。然而，信号和途径直接调节 Drosha在生理或病理应激条件下仍有待鉴定。有多个 一系列证据表明，miRNAs对大脑功能和调节途径特别重要， 以及与遗传性和散发性AD发病机制相关的关键基因。许多miRNAS本身 在AD中改变此外，通过有条件地敲除神经元中的Dicer来抑制miRNA生物合成， 阻断Drosha下游一步的miRNA生物合成， 神经变性和AD样tau过度磷酸化。这可能是最有力的证据， miRNA生物发生与AD之间的潜在联系。然而，这些发现如何转化为动物AD 模型和人类疾病仍有待测试。最近，我们发现各种压力 条件施加直接和严格的控制Drosha。这涉及应激诱导的p38 MAPK依赖性的 Drosha的磷酸化和抑制，并且Drosha的丧失在应激下触发细胞死亡（Molecular Cell in Press）。在一系列的初步研究中，我们已经将这组关键发现扩展到初级皮质神经元 并显示a）应激信号引起p38 MAPK介导的直接磷酸化和Drosha的抑制， B）Aβ似乎参与该通路并降低初级皮质神经元中Drosha的水平; c） 增加Drosha保护神经元免受Aβ诱导的毒性;和d）核Drosha的水平是 在转基因AD大鼠和死后AD脑的皮质中显著降低。所有这些 非常重要的发现支持了一个有趣的假设，即Aβ通过p38 MAPK-Drosha途径信号传导， 抑制miRNA生物合成并干扰神经元稳态和存活。失去德罗沙可能是 部分AD的神经退行性过程。我们建议使用分子和细胞的组合 方法评估Drosha的丢失是否是Aβ诱导的毒性和发病机制的基础， 初级神经元，一个新建立的阿尔茨海默病大鼠模型，和人类死后AD大脑。